Sequential increases in the intrahepatic expression of epidermal growth factor, basic fibroblast growth factor, and transforming growth factor beta in a bile duct ligated rat model of cirrhosis

Abstract

Chronic hepatic regeneration constitutes an important part of the cirrhotic process. The factors regulating chronic hepatic regeneration, however, remain unclear. We therefore analyzed the intrahepatic messenger RNA (mRNA) expression of growth factors (epidermal growth factor [EGF], basic fibroblast growth factor [bFGF], hepatocyte growth factor [HGF], transforming growth factor [TGF]-alpha, and TGF-beta) at progressive time points (postoperative days 2, 7, 14, and 21) in a rat bile duct-ligated (BDL) model of cirrhosis versus sham controls. Intrahepatic growth factor mRNA expression was quantitatively assessed by polymerase chain reaction (PCR) using a dot-blot hybridization technique. Cirrhosis was associated with statistically significant (P < .05) progressive increases in the intrahepatic mRNA expression of bFGF (80-fold), EGF (25-fold), and TGF-beta (fourfold) in BDL animals versus controls. Furthermore, immunohistochemistry of hepatic sections showed a progressive up-regulation of bFGF protein in areas of bile duct proliferation. These areas also showed a dramatic increase in the number of hepatic stellate cells (HSC). In contrast, the intrahepatic expression of hepatocyte growth factor (HGF) mRNA was only significantly increased at postoperative days 7 and 14 in BDL animals before returning to control levels as cirrhosis developed. There were no significant differences found at any timepoint in the expression of TGF-alpha in BDL animals versus controls. In conclusion, the development of cirrhosis in this BDL rat model was associated with a progressive increase in the intrahepatic expression of EGF, bFGF, and TGF-beta. Early increased expression of HGF was not maintained in established cirrhosis. The findings suggest that these growth factors may play important roles in the pathogenesis of chronic hepatic regeneration in cirrhosis.